Prodrugs comprise inactive forms of active drugs where a chemical group is present on the prodrug which renders it inactive and/or confers solubility or some other property to the drug. Prodrugs are generally inactive, but once the chemical group has been cleaved from the prodrug, by heat, cavitation, pressure, and/or enzymes in the surrounding environment, the active drug is generated. Prodrugs may be designed as reversible drug derivatives and utilized as modifiers to enhance drug transport to site-specific tissues. Prodrugs are described in the art, for example, in Sinkula et al., J Pharm. Sci., (1975) 64:181-210, the disclosure of which is hereby incorporated herein by reference in its entirety.
Steroids encompass a variety of compounds having the general cyclopentanoperhydrophenanthrene ring system set forth below. ##STR1##
Steroids cause a variety of therapeutic effects, including enhanced anabolism, e.g., aldosterone, and anti-inflammatory effects, e.g., corticosteroids. Steroids such as cortisone and dexamethasone are potent immune suppressants and are used to treat conditions such as autoimmune diseases, organ transplant rejection, arthritis, skin, mucosal membrane and ophthalmic inflammation, as well as neoplastic conditions such as lymphoma. There are a variety of deleterious side effects associated with prolonged or high doses of steroids, such as fatigue, muscle wasting, bone loss resulting in pathologic fractures, salt and fluid retention, hypertension and heart disease, immunosuppression and infection, and avascular necrosis of the weight bearing articular surfaces of bones, such as the hips.
It is often difficult to deliver appropriate concentrations of steroids to target tissues. For example, in ophthalmic therapy, eye drops may be employed to deliver steroid hormones to the eye. However, the duration of action is short, and less than 3% of the steroid typically penetrates the cornea. As a partial solution to this problem, intraocular injections have been employed to increase the dosage.
The design of steroid prodrugs to date has been to increase the effective water solubility of the steroid. For example, Fedorak, et al., Am. J Physiol, 269:G210-218 (1995), describe dexamethasone-.beta.-D-glucuronide; McLoed, et al., Gastroenterol., 106:405-413 (1994), describe dexamethasone-succinate-dextrans; and Hochhaus, et al, Biomed. Chrom., 6:283-286 (1992), describe dexamethasone-21-sulphobenzoate sodium and dexamethasone-21-isonicotinate.
A new way of delivering higher concentrations of steroids to the target tissue is needed to improve the efficacy of steroids as well as to lessen the side-effects associated with steroid use. The present invention is directed to these, as well as other, ends.
SUMMARY OF THE INVENTION
The present invention is directed to a compound comprising a steroid covalently bonded to a lipid moiety via a linking group.
In another embodiment, the compound comprising a steroid covalently bonded to a lipid moiety via a linking group may be of formula (I): EQU D--X--L (I)
wherein:
D is a steroid; PA1 X is a linking group comprising an ester group, a carbamate group, a carbonyl group, a thioester group, a disulfide group, an ether group, an anhydride group, or an amide group; and PA1 L is a lipid moiety comprising an acyl, alky, alkylaryl, fluoroacyl, fluoroalkyl or fluoroalkylaryl group having from about 4 to about 40 carbon atoms. PA1 X.sub.2 is a direct bond, --C(.dbd.X.sub.4)--, --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--, --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3, --X.sub.3 --C(.dbd.X.sub.4)--R.sub.5 --, --C(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --, --X.sub.3 --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, --C(.dbd.X.sub.4)--R.sub.5 --C(.dbd.X.sub.4)--, --(.dbd.X.sub.4)--R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, or --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--; PA1 each X.sub.3 is independently --O--, --NR.sub.4 -- or --S--; PA1 each X.sub.4 is independently O or S; PA1 M is --R.sub.5 --X.sub.3 --, --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--, --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, --R.sub.5 --X.sub.3 --(YX.sub.4)P(.dbd.X.sub.4)--X.sub.3 -- or --X.sub.3 --(YX.sub.4)P(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --; PA1 Y is a hydrogen atom or a pharmaceutically acceptable counter ion; PA1 D is a steroid; PA1 each n is independently an integer of 0 or 1; PA1 each R.sub.1 is independently an alkyl group of 1 to about 50 carbon atoms that is optionally substituted with one or more halogen atoms; PA1 each R.sub.2 is independently an alkylene group of 1 to about 30 carbon atoms that is optionally substituted with one or more halogen atoms; PA1 each of R.sub.3 and R.sub.4 is independently .dbd.O, a hydrogen atom or an alkyl group of 1 to about 10 carbon atoms; and PA1 each R.sub.5 is independently a direct bond or an alkylene group of 1 to about 30 carbon atoms. PA1 D is a steroid; PA1 X is a linking group comprising an ester group, a carbamate group, a carbonyl group, a thioester group, a disulfide group, an ether group, an anhydride group, or an amide group; and PA1 L is a lipid moiety comprising an acyl, alkyl, alkylaryl, fluoracyl, fluoroalkyl or fluoroalkylaryl group having from about 4 to about 40 carbon atoms. PA1 each n is independently an integer of 0 or 1; PA1 X.sub.2 is a direct bond, --C(.dbd.X.sub.4)--, --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--, --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3, --X.sub.3 --C(.dbd.X.sub.4)--R.sub.5 --, --C(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --, --X.sub.3 --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, C(.dbd.X.sub.4)--R.sub.5 --C(.dbd.X.sub.4)--, --R.sub.5 --X.sub.3 C(.dbd.X.sub.4)--R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, --C(.dbd.X.sub.4)R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 -- or --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--; PA1 each X.sub.3 is independently --O--, --NR.sub.4 -- or --S--; PA1 each X.sub.4 is independently O or S; PA1 M is --R.sub.5 --X.sub.3 --, --R.sub.5 --X.sub.3 --C(.dbd.X.sub.4)--, --R.sub.5 --C(.dbd.X.sub.4)--X.sub.3 --, --R.sub.5 --X.sub.3 --(YX.sub.4)P(.dbd.X.sub.4)--X.sub.3 -- or --X.sub.3 --(YX.sub.4)P(.dbd.X.sub.4)--X.sub.3 --R.sub.5 --; PA1 Y is hydrogen or a pharmaceutically acceptable counter ion; PA1 D is a steroid; PA1 each R.sub.1 is independently an alkyl group of 1 to about 50 carbon atoms that is optionally substituted with one or more halogen atoms; PA1 each R.sub.2 is independently an alkylene group of 1 to about 30 carbon atoms that is optionally substituted with one or more halogen atoms; PA1 each of R.sub.3 and R.sub.4 is independently .dbd.O, a hydrogen atom or an alkyl group of 1 to about 10 carbon atoms; and PA1 each R.sub.5 is independently a direct bond or an alkylene group of 1 to about 30 carbon atoms. PA1 R.sup.2 is R', .dbd.O, OR', R'--N--(R').sub.2, SR', C(.dbd.O)R', C(.dbd.O)OR', C(.dbd.S)OR', C(.dbd.O)SR', OC(.dbd.O)R', OOC(C.sub.6 H.sub.5); PA1 R' is a hydrogen atom or a C.sub.1 to C.sub.60 saturated or unsaturated linear or branched hydrocarbon chain, optionally interrupted with O, S, P or N, and optionally substituted with halogen atoms; PA1 R.sup.3 is a saturated or unsaturated double bond; PA1 R.sup.4 is a halogen atom or R'; PA1 n is an integer of 0 or 1; PA1 R.sup.5 is R' or a halogen atom; PA1 R.sup.6 is R' or an unsaturated double bond; PA1 R.sup.7 is R' or a halogen atom; PA1 R.sup.8 is R' or an unsaturated double bond; PA1 R.sup.9 is .dbd.O, OH, R' or a halogen atom; PA1 R.sup.10 is R', a halogen atom or OH; PA1 R.sup.11 is R' or C(.dbd.O)H; PA1 R.sup.12 is R', OH, OCOR' or .dbd.CH.sub.2 ; PA1 R.sup.13 is R', .dbd.O, OH, OC(.dbd.O)R', C(.dbd.O)CH.sub.2 OR', C(.dbd.O)CH.sub.3 ; C(.dbd.O)OR', CCH, or an alkyl halide group; and PA1 R.sup.14 is R', OH, CCH, CCCH3, or OC(.dbd.O)R'. PA1 L is a lipid, protein, polymer, carbohydrate, surfactant or the like; PA1 P is a hydrophilic polymer; and PA1 T is a targeting ligand. PA1 each of X.sub.2 and X.sub.3 is independently a direct bond, --R.sub.5 --X.sub.4 --C(.dbd.X.sub.5)--, --R.sub.5 --C(.dbd.X.sub.5)--X.sub.4, --X.sub.4 --C(.dbd.X.sub.5)--R.sub.5 --, --C(.dbd.X.sub.5)--X.sub.4 --R.sub.5 --, --X.sub.4 --R.sub.5 --C(.dbd.X.sub.5)--X.sub.4 --, --R.sub.5 --X.sub.4 --C(.dbd.X.sub.5)--R.sub.5 --C(.dbd.X.sub.5)--X.sub.4 -- or --R.sub.5 --C(.dbd.X.sub.5)--X.sub.4 --R.sub.5 --X.sub.4 --C(.dbd.X.sub.5)--; PA1 each X.sub.4 is independently --O--, --NR.sub.4 -- or --S--; PA1 each X.sub.5 is independently O or S; PA1 M is --R.sub.5 --X.sub.4 --C(.dbd.X.sub.5)--, --R.sub.5 --C(.dbd.X.sub.5)--X.sub.4 --, --R.sub.5 --X.sub.4 --(YX.sub.5)P(.dbd.X.sub.5)--X.sub.4 -- or --X.sub.4 --(YX.sub.5)P(.dbd.X.sub.5)--X.sub.4 --R.sub.5 --; PA1 each n is, independently, 0 or 1; PA1 Y is hydrogen or a pharmaceutically acceptable counter ion; PA1 Z is a hydrophilic polymer; PA1 Q is a targeting ligand or a precursor to a targeting ligand; PA1 each R.sub.1 is independently an alkyl group of 1 to about 50 carbons that may optionally be substituted with one or more halogen atoms; PA1 each R.sub.2 is independently an alkylene group of 1 to about 30 carbons that may optionally be substituted with one or more halogen atoms; PA1 each of R.sub.3 and R.sub.4 is independently hydrogen or alkyl of 1 to about 10 carbons; and PA1 each R.sub.5 is independently a direct bond or alkylene of 1 to about 30 carbons. PA1 (a) vortexing and/or shaking an aqueous mixture of gaseous precursor and additional materials as desired, including, for example, stabilizing materials, thickening agents and/or dispersing agents. Optional variations of this method include autoclaving before vortexing or shaking; heating an aqueous mixture of gaseous precursor; venting the vessel containing the mixture/suspension; shaking or permitting the gaseous precursor filled vesicle to form spontaneously and cooling down the suspension of gaseous precursor filled vesicles; and extruding an aqueous suspension of gaseous precursor through a filter of about 0.22 .mu.m. Alternatively, filtering may be performed during in vivo administration of the vesicles such that a filter of about 0.22 .mu.m is employed; PA1 (b) microemulsification whereby an aqueous mixture of gaseous precursor is emulsified by agitation and heated to form, for example, vesicles prior to administration to a patient; PA1 (d) utilizing in any of the above methods a sealed vessel to hold the aqueous suspension of gaseous precursor and maintaining the suspension at a temperature below the phase transition temperature of the gaseous precursor, followed by autoclaving to raise the temperature above the phase transition temperature, optionally with shaking, or permitting the gaseous precursor vesicle to form spontaneously, whereby the expanded gaseous precursor in the sealed vessel increases the pressure in the vessel, and cooling down the gas filled vesicle suspension, after which shaking may also take place.
In another embodiment, the compound comprising a steroid covalently bonded to a lipid moiety via a linking group may be a compound of the formula (II), which is within the scope of formula (I): ##STR2## wherein: each X.sub.1 is independently a direct bond, --O--, --S--, --SO--, --SO.sub.2 --, --NR.sub.4 --, --X.sub.3 --C(.dbd.X.sub.4)--, --C(.dbd.X.sub.4)--X.sub.3 -- or --C(.dbd.X.sub.4)--;
Another embodiment of the invention is directed to a composition comprising, in an aqueous carrier, a steroid covalently bonded to a lipid moiety via a linking group.
Another embodiment of the invention provides a method of delivering a steroid to a patient comprising administering to the patient a composition comprising a steroid covalently bonded to a lipid moiety via a linking group. If desired, the method may further comprise the step of imaging the patient with diagnostic ultrasound to monitor the location of the composition in the patient. Also, if desired, the method may comprise the step of applying therapeutic ultrasound to the patient to facilitate localization of the steroid in a desired region of the patient.
The steroid covalently bonded to the lipid moiety via the linking group may be, for example, a compound of formula (I) or formula (II) above. The lipid moiety that is covalently bonded to the steroid via a linking group may form a vesicle or may be non-vesicular, as desired. The compositions of the invention may also comprise a wide variety of components, including, for example, one or more of gases, gaseous precursors, liquids, stabilizing materials, targeting ligands and other bioactive agents. The stabilizing materials may comprise, for example, lipids, proteins, polymers, surfactants, and the like. The stabilizing materials may be in the form of a vesicle or may be non-vesicular forming. for example, an emulsion, suspension, dispersion or the like.
These and other aspects of the invention will become more apparent from the following detailed description.